Apparatus and method for optimized stimulation of a neurological target

ABSTRACT

A preferred frequency is identified, being usable to stimulate a neurological target within a mammalian body using at least one microelectrode positioned at or near the target. To establish efficient and effective stimulation, an impedance analyzer is provided for measuring electrical impedance values indicative of a microelectrode-tissue interface across a range of different frequencies. A preferred one of the measured electrical impedance values is identified as being closest to a pure resistance. The neurological target can then be stimulated at or near the frequency associated with the preferred impedance value (peak resistance frequency), thereby promoting desirable traits, such as optimum charge transfer, minimum signal distortion, increased stimulation efficiency, and prevention of microelectrode corrosion. The peak resistance frequency can be used to determine an preferred pulse shape. A target can be identified by microelectrode measurements of neuronal activity and/or impedance magnitude at peak resistance frequency.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority under 35 U.S.C. §120 as a continuation of U.S. patent application Ser. No. 14/731,296,titled “APPARATUS AND METHOD FOR OPTIMIZED STIMULATION OF A NEUROLOGICALTARGET” and filed Jun. 4, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/316,154, titled “APPARATUS AND METHOD FOROPTIMIZED STIMULATION OF A NEUROLOGICAL TARGET,” which was filed on Jun.26, 2014, which is a divisional of U.S. patent application Ser. No.13/056,261, titled “APPARATUS AND METHOD FOR OPTIMIZED STIMULATION OF ANEUROLOGICAL TARGET,” which was filed on May 9, 2011, which is the U.S.national stage application of PCT International Application No.PCT/US2009/052077, titled “APPARATUS AND METHOD FOR OPTIMIZEDSTIMULATION OF A NEUROLOGICAL TARGET” filed on Jul. 29, 2009, whichclaims priority to U.S. Provisional Application No. 61/084,870, titled“APPARATUS AND METHOD FOR OPTIMIZED STIMULATION OF A NEUROLOGICALTARGET” filed on Jul. 30, 2008. The contents of the foregoingapplications are hereby incorporated by reference in their entireties.

FIELD

The apparatus and method described herein relate generally to the use ofconductive electrodes to stimulate tissue in a mammalian body. Morespecifically, the apparatus and method relate to use of conductiveelectrodes to stimulate a neurological target.

BACKGROUND

Neurostimulation is used effectively today to treat several diseases byplacing electrodes in contact with neural tissue. Medical devices usedin the course of neurostimulation generally transfer one or more ofelectric charge and electric fields to tissue, resulting inphysiological change, which benefits the patient, or performs aphysiological measurement. For example, electrical neurostimulation isused in the cochlea to produce responses similar to those produced fromaudible sounds. As another example, electrodes are placed near ananimal's spine and configured to generate electrical pulses to treatpain. As another example, electrodes are placed in the deep brain forstimulation neurological targets including the subthalamic nucleus, theglobus pallidus, configured to generate electrical pulses to treat thesymptoms of movement disorders, such as Parkinson's disease, EssentialTremor or Dystonia. Such therapies may also treat the symptoms ofEpilepsy and other neurological disorders. Neurostimulation is also usedin other parts of the body, such as the retina, and the peripheralnervous system.

The localization of such electrical stimulation is important, and leadsto higher efficiency in the therapy. Higher localization of theelectrical stimulation generally requires smaller electrodes. Thesmaller electrodes exhibit particular electrical characteristics onceplaced into contact with an electrolyte such as the physiological fluidin the body.

The stimulation signals used in electrical stimulation can be fullydescribed by their amplitude, pulse shape, and pulse frequency. Signalamplitudes are generally measured in units of voltage or current. Pulseshapes are generally described by their geometric shape and pulse width.For example, a commonly used pulse shape is a rectangular pulse with apulse width, measured in units of time, such as micro-seconds. Finally,pulse repetition frequency generally describes the number of pulses persecond applied to the electrodes. For example, a rectangular pulse ofwidth 50 micro-seconds can be applied to an electrode at a frequency of130 Hz. A suitable combination of amplitude, pulse shape, and pulserepetition frequency providing effective treatment is generallydifficult to determine.

Several attempts to increase stimulation efficiency have been made. Themethods used, however, have a direct effect on power consumption, tissuenarcosis, and would potentially degrade the electrode materials due tocorrosion. Empirical and simulation methods have been used to find astimulation amplitude “threshold” at a particular frequency, such as 1kHz or 10 kHz. Threshold determination techniques are explained byPalanker et al. and Jensen et al. empirically in the case of retinalstimulation.

The electrical stimulation of tissue with micro-scale electrodespresents several problems that have been previously identified, but havenot been properly addressed. First, the interface impedance between amicroelectrode and the surrounding tissue is extremely high, usually onthe order of 1 MO for a 50 diameter electrode at biologicallysignificant frequencies of 1 kHz. Such a high impedance leads to a highcurrent requirement in order to achieve a sufficient voltage across theneural tissue for activation. Such high current can destroy theelectrode material because it is susceptible to corrosion in thegenerally electrolytic environment of physiological fluid. Suchcorrosion would be undesirable as dangerous toxins can be released intothe tissue. Furthermore, high currents will quickly decrease batterylife for implantable devices.

SUMMARY

A system and method is described herein to identify a preferredfrequency, and/or pulse shape, and/or amplitude, for electrical neuronstimulation. An electrical impedance is measured for at least onemicroelectrode positioned at a neurological target. The measurement isrepeated across a span of different frequencies, with one of themeasured electrical impedance values identified as being closest to apure resistance. The measured frequency at which the identifiedimpedance was obtained is referred to herein as a “peak resistancefrequency.” The parameters of a stimulation signal, i.e., the amplitude,pulse shape, and pulse frequency, can be determined and in someinstances optimized using the characteristics of the peak resistancefrequency. A signal having a substantial spectral content, energy, at orvery close to the peak resistance frequency is subsequently applied tothe at least one microelectrode to therapeutically stimulate tissue(neurons) at this frequency.

One embodiment of the invention relates to a process for stimulating aneurological target with at least one microelectrode with a preferredpulse shape. According to the process a respective electrical impedancevalue indicative of the microelectrode-tissue interface impedance ismeasured through each of several microelectrodes at each of severalfrequencies. A peak resistance frequency is identified from theelectrical impedance values for each of the at least onemicroelectrodes. A preferred stimulation pulse shape is identifiedhaving a pulse width less than the inverse of the peak resistancefrequency. In the case of a uni-polar pulse, such as a rectangular wave,the pulse width can be equal to half the inverse of the peak resistancefrequency. The identified target can then be stimulated with thepreferred pulse shape using a physiologically relevant pulse frequencywhich is not necessarily equal to the peak resistance frequency.

One embodiment of the invention relates to a device for stimulating aneurological target, including at least one microelectrode, an impedanceanalyzer, and a preferred-frequency detector. The impedance analyzer isin electrical communication with each of the at least onemicroelectrodes, which are, in turn, positionable at the neurologicaltarget. The impedance analyzer is configured to measure a respectiveelectrical impedance value indicative of a microelectrode-tissueinterface at each of a several different frequencies for each of the atleast one microelectrodes. The preferred-frequency detector is incommunication with the impedance analyzer and configured to detect fromamong the electrical impedance values measured at each of the at leastone microelectrodes, a respective preferred frequency. In at least someembodiments, the preferred frequency is determined according to themeasured impedance value having a minimum phase angle. The stimulationsource is in communication with the at least one microelectrode andconfigured to stimulate the neurological target at the respectivepreferred frequency.

Another embodiment of the invention relates to a process for stimulatinga neurological target with at least one microelectrode. According to theprocess, respective electrical impedance values indicative of theimpedance of the microelectrode-tissue interface are measured throughthe at least one microelectrode, at each of several differentfrequencies. A preferred stimulation frequency is identified from theelectrical impedance values, and the neurological target is stimulatedat the preferred stimulation frequency.

Yet another embodiment of the invention relates to a process forstimulating a neurological target with at least one microelectrode.According to the process, respective electrical impedance values aremeasured through each of the at least one microelectrodes. The measuredelectrical impedance values are indicative of the microelectrode-tissueinterface impedance at each of several different frequencies. Apreferred stimulation frequency is identified for each of the at leastone microelectrodes from the respective electrical impedance values. Apreferred stimulation amplitude is identified at the preferredstimulation frequency for each of the at least one microelectrodes. Theneurological target can then be stimulated at the preferred stimulationfrequency and at the preferred stimulation amplitude.

Yet another embodiment of the invention relates to a process forstimulating a neurological target with at least one microelectrode.According to the process a respective electrical impedance valueindicative of the microelectrode-tissue interface impedance is measuredthrough each of several microelectrodes at each of several differentfrequencies. A peak resistance frequency is identified from theelectrical impedance values for each of the at least onemicroelectrodes. A preferred stimulation pulse shape and amplitude aredetermined using the respective peak resistance frequency. The pulseshape is determined as described above, and its amplitude can bedetermined as inversely proportional to the impedance magnitude at thepeak resistance frequency. The identified target can then be stimulatedwith the preferred pulse shape and amplitude, using either the peakresistance frequency, or a physiologically relevant pulse frequency.

Yet another embodiment of the invention relates to a process forstimulating a neurological target with at least one microelectrode.According to the process, a respective electrical impedance valueindicative of the microelectrode-tissue interface impedance is measuredthrough each of several microelectrodes at each of several differentfrequencies. A peak resistance frequency is identified from theelectrical impedance values for each of a plurality of microelectrodes.One or more of the microelectrodes is identified from the respectivepeak resistance frequencies as being positioned at the neurologicaltarget.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1 is a functional block diagram of an exemplary embodiment of aneurological target stimulator.

FIG. 2 is a cross-sectional view of a portion of an anatomy illustratingan exemplary microelectrode structure positioned at a neurologicaltarget.

FIG. 3 is a functional block diagram of an exemplary alternativeembodiment of a neurological target stimulator.

FIG. 4 is a schematic illustration of an exemplary embodiment of a statemachine for controlling operational modes of a neurological stimulator.

FIG. 5A and FIG. 5B respectively illustrate magnitude and phase resultsobtained from an impedance spectroscopy sweep of an exemplarymicroelectrode-tissue interface obtained from microelectrodes of animplanted neurological target stimulator.

FIG. 5C and FIG. 5D respectively illustrate magnitude and phase resultsobtained from an impedance spectroscopy sweep of another exemplarymicroelectrode-tissue interface obtained from microelectrodes of animplanted neurological target stimulator.

FIG. 6A is a cross-sectional view of a microelectrode-tissue interfacefor an exemplary microelectrode.

FIG. 6B is an exemplary circuit model approximating an impedanceresponse of a microelectrode-tissue interface for an exemplarymicroelectrode.

FIG. 7 is a flow diagram of an exemplary process for determining andstimulating a neurological target at a preferred stimulation frequency.

FIG. 8 is a functional block diagram of an exemplary embodiment of aneurological target stimulator configured in a stimulation mode.

FIG. 9 is a functional block diagram of an exemplary embodiment of aneurological target stimulator having multiple tunable stimulationsources.

FIG. 10 is a functional block diagram of an exemplary embodiment of aneurological target stimulator configured for obtaining stimulationsource signals from a pulse source.

FIG. 11 is a schematic diagram of an exemplary embodiment of a bandpassfilter positionable in electrical communication between a stimulationsource and at least one microelectrode.

FIG. 12 illustrate a plot of representative performance curves for anexemplary bandpass filter implemented using a Butterworth design.

FIG. 13A illustrates plots of an exemplary pulse signal and an exemplarystimulation signal obtained therefrom after filtering.

FIG. 13B illustrates a zoom-out of the filtered signal of FIG. 13A and aseries of similarly filtered pulses.

FIG. 14 is a functional block diagram of an exemplary embodiment of aneurological target stimulator configured for obtaining stimulationsource signals from a pulse source.

FIG. 15 is a perspective view of a portion of a human anatomyillustrating an exemplary neurological target stimulator implantedtherein.

FIG. 16 is a top view of an exemplary embodiment of a neurologicaltarget stimulator.

FIG. 17 is a top view of an exemplary alternative embodiment of aneurological target stimulator.

FIG. 18 is a flow diagram of an exemplary process for identifyingimplanted microelectrodes usable for stimulation of a neurologicaltarget.

FIG. 19 is a functional block diagram of an exemplary alternativeembodiment of a neurological target stimulator.

FIG. 20 is a schematic illustration of an exemplary embodiment of astate machine for controlling operational modes of a neurologicalstimulator.

FIG. 21 is a flow diagram of an alternative exemplary process foridentifying implanted microelectrodes usable for stimulation of aneurological target.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The identification of the peak resistance frequency is a simple conceptfrom impedance spectroscopy but is new to the field of neuronalstimulation at least because it has not yet been applied tomicroelectrodes. After implantation of microelectrodes at a targetneurological site within a live animal, a tissue reaction progressivelyforms around the microelectrode array. The tissue reaction has beenobserved to change substantially within a period immediately followingimplantation, subsequently stabilizing after this initial period. Thistissue reaction tends to alter electrical current flow for theindividual microelectrodes, as their respective microenvironment varies.In general, the impedance of a respective microelectrode-tissueinterface is substantially different for each microelectrode of an arrayof microelectrodes.

Using a technique referred to herein as electrical impedancespectroscopy, it is possible to identify a preferred frequency for eachmicroelectrode at which the electrical impedance of the microelectrodeis most resistive and least capacitive given the surrounding tissue.Stimulation of the neurological site performed at or near thisfrequency, promotes minimal signal distortion, and maximum chargetransfer to the surrounding tissue. There will be minimal signaldistortion, because the capacitive components of themicroelectrode-tissue interface have a minimal effect on the signalcomponents, and maximum charge transfer because themicroelectrode-tissue interface is mostly resistive. In someembodiments, various aspects of a stimulation signal can be adjusted. Ifstimulation at this frequency is not physiologically effective, or ifthe stimulation source is not enabled to deliver such a frequency,attributes of the pulse, such as its shape, can be optimized instead.The pulse shape can be adapted to have substantial spectral content nearor equal to the peak resistance frequency by filtering it, or byotherwise setting the pulse width equal to about half of the inverse ofthe peak resistance frequency. The resulting filtered signal will leadto reduced distortion, and enhanced charge transfer.

Referring to FIG. 1, a functional block diagram of an exemplaryembodiment of a neurological target stimulator 114 is shown. Thestimulator 114 includes at least one microelectrode 115 positionable ata neurological target of interest. The stimulator 114 also includes animpedance analyzer 116 configured for measuring an electrical impedance,a preferred frequency detector 117, and a stimulator 118 forelectrically stimulating the neurological target.

The impedance analyzer 116 can use any of various known techniques formeasuring electrical impedance. Generally, the impedance analyzer 116provides a test electrical signal having known or measurable attributesto the microelectrode-tissue interface. Such attributes include avoltage level of a voltage source, or a current level of a currentsource. The test voltage or current, as the case may be, when applied tothe microelectrode-tissue interface, induces a sensed current or voltageaccording to physical properties of the microelectrode-tissue interface.The impedance analyzer 116 can form a ratio of the test signal to thesensed signal, yielding an impedance value according to Ohm's Law:Z=V/I. As the microelectrode-tissue impedance Z is a complex quantity,each of the test and sensed electrical signals is identified as havingboth a magnitude and a phase.

In operation, the impedance analyzer measures a complex impedance of themicroelectrode-tissue interface surrounding the at least onemicroelectrode 115. The impedance analyzer repeats the measurements atmultiple different frequencies, by varying frequency of the applied testelectrical signal. Preferably, the multiple frequencies span a frequencyrange that includes biologically relevant frequencies. The preferredfrequency detector 117 identifies the measured impedance being closestto a pure resistance. Such a determination can be accomplished byidentifying the measured impedance value having a phase value closest tozero. For example, a measured impedance can be identified having minimumabsolute value phase (i.e., MIN|∠Z|). Such a determination can also beaccomplished by identifying the measured impedance value having aminimum reactance (i.e., MIN(Im{Z})). The frequency at which theimpedance determined to be closest to a pure resistance is identified asthe peak resistance frequency. The stimulator 118 is then adjusted toprovide a stimulation signal at a frequency, or frequency band, at ornear the preferred stimulation frequency. Alternatively or in addition,if a physiologically relevant pulse frequency is known, the stimulator118 is adjusted to provide a stimulation signal with a pulse shape thathas substantial spectral content equal to or near the peak resistancefrequency. This preferred pulse shape is then delivered at thepre-determined pulse repetition frequency. Alternatively, if aphysiologically relevant pulse frequency is known, and the stimulator118 provides a pre-determined pulse shape, the temporal characteristicsof the pulse shape can be tuned so that a substantial spectral contentis provided at or near the preferred stimulation frequency. For example,for a stimulator delivering a substantially rectangular pulse, the pulsewidth of the rectangular pulse would be tuned to be equal to half theinverse of the peak resistance frequency. This preferred pulse width isthen delivered at the pre-determined pulse frequency. As anotherexample, for a stimulator delivering a biphasic charge balanced squarepulse, the pulse width of the stimulation pulse, whether leading orlagging, would be tuned to be equal to half the inverse of the peakresistance frequency. This preferred pulse width is then delivered atthe pre-determined pulse frequency. The stimulation signal is thenapplied to the at least one microelectrode 115.

Referring to FIG. 2, a cross-sectional view of a portion of an anatomy108 is shown, illustrating an exemplary microelectrode probe 100positioned at a neurological target 110. The probe 100 includes an arrayof microelectrodes 102 distributed along a supporting structure 104.Preferably, the probe 100 is shaped and sized to allow one or more ofthe microelectrodes 102 to be positioned adjacent the neurologicaltarget 110. To this end, materials used in construction of a probe, aswell as construction features, size, and shape can be selected forbiocompatibility. As illustrated, one or more microelectrodes 112 of themicroelectrode probe are positioned in contact with the neurologicaltarget 110.

The supporting structure 104 can be a rigid, or semi-rigid structure,such as a polymeric cylinder. Alternatively or in addition, thestructure can be a flexible structure, such as one or more flexiblesubstantially non-conducting layers (i.e., a dielectric ribbon) ontowhich the microelectrodes 102 are formed as electrically conductive filmlayers. The one or more microelectrodes 102 are in communication withelectronic circuitry (not shown) through one or more electrical leads106 that can be routed through an internal lumen of a cylindricalsupporting structure 103 and/or formed using elongated film layers alonga flexible, ribbon-like supporting structure 104.

The microelectrodes can be placed in the brain generally for stimulationof the cortex and for deep brain stimulation of neurological targetsincluding the subthalamic nucleus, the globus pallidus. Themicroelectrodes can also be placed in other parts of the body, such asthe retina, the peripheral nervous system for neurostimulation of suchportions of an animal anatomy. Although microelectrodes are discussedgenerally throughout the various embodiments, there is no intention tolimit the upper or lower size of the microelectrodes. The devices andmethods described herein are generally scalable, with an microelectrodesize determined according to the intended application. For at least someof the neurological applications, microelectrodes are dimensionedsub-millimeter. In some embodiments, microelectrodes are dimensionedsubmicron. In some embodiments, the microelectrodes are formed as planerstructures having a diameter of about 50 pm that are arranged in alinear array with center-to-center spacing of about 100 pm. The planerstructures of the microelectrodes can have regular shapes, such ascircles, ellipses, polygons, irregular shapes, or a combination ofregular and irregular shapes.

This device is implantable near a neurological target, such as a targetbrain structure, using common neurosurgical techniques such asstereotaxy or endoscopy. The device might be inserted without support,or within a cannula, which has an inner dimension smaller than the outerdimension of the device. The cannula would then be retracted once thedevice is in position. Alternatively, the device can be inserted with orwithout support from a cannula, but with a central rigid rod of outerdiameter smaller than the inner diameter of a lumen in the device. Therigid rod, or stylet, is retracted once the device is in position.

The operator can connect the microelectrodes to a recording unit that isconfigured to identify certain regions of the neurological target (e.g.,the brain) according to their electrical activity. The microelectrodesused to record from the neurological target can be the samemicroelectrodes as those used to stimulate the target. Alternatively orin addition, the microelectrodes used to record from the neurologicaltarget can be separate microelectrodes from those used to stimulate thetarget. As microelectrodes destined for recording may differ in one ormore of size, shape, number, and arrangement, from those microelectrodesdestined for stimulation, using different microelectrodes.

The microelectrodes can be connected to a stimulation source through oneor more interconnecting leads. In some embodiments, at least a portionof the stimulation source can be extracorporeal. Alternatively or inaddition, the stimulation source can be fully implanted within the body.Any implanted elements of the stimulation source are fabricated and/orcontained with a hermetically sealed biocompatible envelop. Suchbiocompatible packaging of signal sources is well known, for example, inthe area of artificial pacemakers.

The stimulation source may be a controllable signal generator, producinga desired signal according to a prescribed input. For example, thesignal generator may receive an input indicative of a desired outputstimulation signal frequency. Such output stimulation signals can have avariety of waveforms, such as pulses, charge balanced pulses,sinusoidal, square-wave, triangular-wave, and combinations of thesebasic waveforms. In some embodiments, the stimulation source includes apulse generator for applying signals to the microelectrode site. Thesignals from the pulse generator can be connected directly to themicroelectrodes, or they can be preprocessed using electronics. In someembodiments, such preprocessing electronics are embedded within theimplantable device. The preprocessing electronics can filter certainparts of the original signal in order to transmit only the frequencycomponents of the original signal that are at or near the PeakResistance Frequency of the microelectrode. For embodiments in whichthere are more microelectrodes than signals, the electronics can routethe stimulation signals to preferred one or more of the microelectrodes.

A more detailed functional block diagram of an exemplary embodiment of aneurological target stimulator 124 is shown in FIG. 3. The stimulator124 includes a microelectrode array 120 having at least onemicroelectrode 122 positionable at a neurological target of interest.The stimulator 124 also includes an impedance analyzer 128 configuredfor measuring an electrical impedance and a stimulator 130 forelectrically stimulating the neurological target. Each of the impedanceanalyzer 128 and the stimulator can be electrically coupled to one ormore microelectrodes 122 of the microelectrode array 120.

In some embodiments, the stimulator 124 includes a signal router 126 asshown for selectively coupling one or more of the impedance analyzer 128and the stimulator 130 to one or more microelectrodes 122. The signalrouter 126 can include a routing network for conveying electricalsignals between one or more of the microelectrodes 122 and one or moreof the impedance analyzer 128 and the stimulator 130. For example, thesignal router 126 can include an electrically conductive branch circuitconnecting each of the microelectrodes 122 to one or more of theimpedance analyzer 128 and the stimulator. One or more switches can beincluded within such a conductive branch circuit for making or breakinga conductive path along the electrically conductive branch. Suchswitches allow for selective interconnection of one or more of themicroelectrodes 122 to one or more of the impedance analyzer 128 and thestimulator 130. Such switches can be fabricated using one or more ofmicro-machined switches, such as micro-machined reed relays.Alternatively or in addition, one or more of the switches can beimplemented using electronic switches, such as transistors.

The stimulator 124 also includes a processor 132 in communication withone or more of the impedance analyzer 128, the stimulator 130, and thesignal router 126. The processor 132 can include one or moremicroprocessors, configured to control one or more of the impedanceanalyzer 128, the stimulator 130, and the signal router 126 according topre-programmed instruction. The processor 132 can include aninput/output port 133. Such a port 133 can be used to uploadpreprogrammed instruction, to obtain measured results, such as measuredelectrical impedance values, and to review settings of one or more ofthe impedance analyzer 128, the stimulator 130, and the signal router126. The processor 132 can be in further communication with a memory 134for storing one or more of preprogrammed instructions, measured results,and instrument settings.

The stimulator 124 can include one or more additional functionalelements, such as a micro electrode selector 135, a peak resistancefrequency detector 137, an instrument controller 138, and in someinstance, a power manager 139 (shown in phantom). One or more of theseadditional functional elements 135, 137, 138, 139 can be implemented inhardware, firmware, software, or a combination of one or more ofhardware, firmware, and software. In the exemplary embodiment, each ofthese additional functional elements 135, 137, 138, 139 is implementedas a processes running on the microprocessor 132. An executive process131 can be provided to coordinate operation of the stimulator 124,including operation of the one or more additional functional elements135, 137, 138, 139, when provided.

A memory 134, when provided, can be used to store, at least temporarily,measured impedance values for each of the at least one microelectrodes122. Alternatively or in addition, the memory 134 can be used to storethe peak resistance frequency determined for each of the at least onemicroelectrodes 122. The memory 134 can include one or more memoryelements, such as random access memory (RAM), optical disk storage,magnetic disk storage, and flash memory. The memory 134 can beconfigured as a single element, or distributed, as in an on-chipprocessor memory and a separate memory chip.

The stimulator 124 also includes a power source 136 for providing powerto one or more of the impedance analyzer 128, the stimulator 130, thesignal router 126, and the processor 132. In some embodiments, the powersource 136 is implantable within an animal body. Alternatively or inaddition, at least a portion of the power source 136 can reside excorporeal. The power source 136 can include an electrical storageelement, such as a storage capacitor. Alternatively or in addition, thepower source 136 can include an electrochemical storage element, such asa battery. Alternatively or in addition, the power source 136 caninclude an electromechanical power conversion element based on magneticinduction. The power source 136 can also include power conditioningcircuitry configured to implement one or more of rectification,regulation, and filtration. In some embodiments, the power source isrechargeable.

In some embodiments, the processor 132 implements a state machine, suchas the exemplary state machine illustrated in FIG. 4. The state machinecan be used to select different operational modes of the stimulator 124as described in reference to FIG. 3. For example, in a first mode orstate, the stimulator 124 is configured to measure electrical impedancevalues through the microelectrode array 120. In this mode, the processor132 enables the impedance analyzer 128 and the signal router 126 toplace the impedance analyzer 128 in electrical communication with aselected one of the one or more microelectrodes 122. In a second mode orstate, the stimulator 124 is configured to determine a peak resistancefrequency for one or more of the microelectrodes 122 of themicroelectrode array 120. In a third mode or state, the stimulator 124is configured to stimulate the neurological target one or more of themicroelectrodes 122 tuned to a respective peak resistance frequency, orstimulated with a preferred pulse shape as determined by the peakresistance frequency. In the third mode of the exemplary state machine,the processor disables the impedance analyzer 128 and enables thestimulator 130 prior to application of the stimulation signal.

Measured impedance results are provided in FIG. 5A illustrating themeasured impedance magnitude 140 and FIG. 5B illustrating the measuredimpedance phase 144. In particular, magnitude and phase results obtainedfrom an impedance spectroscopy sweep are illustrated of an exemplarymicroelectrode-tissue interface. The magnitude and phase togetherdescribe a phasor representing a complex impedance value—a ratio of ameasured voltage phasor to a measured electric current phasor.Alternatively, the same complex electrical impedance can be portrayeddifferently, such as a combination of real (i.e., resistance) andimaginary (i.e., reactance) values. Alternatively or in addition, anadmittance spectroscopy sweep can be obtained for the samemicroelectrode-tissue interface. The admittance is essentially aninverse of the impedance, with a real component reflecting aconductance, and an imaginary component reflecting a susceptance. A peakresistance frequency would be the frequency associated with theadmittance being closest to a pure conductance. Although theillustrative embodiments are directed towards impedance, they are notintended to be limiting. Namely, the methods and devices describedherein could be implemented to measure admittance without departing fromthe scope of the invention.

The electrical impedance spectroscopy sweep is performed for severalsample frequencies distributed across a frequency range defined betweena lower frequency limit 141 and an upper frequency limit 143. Thefrequency spacing between adjacent frequency samples can be constant(e.g., the frequency range divided by the number of samples−1), or varyaccording to frequency of the sample. In some embodiments, the frequencyspacing between adjacent frequency samples is determined according to acommon logarithm of the sample's frequency. The exemplary impedancespectroscopy sweep was performed at one microelectrode site between 100Hz and 1 MHz. This sweep includes the neurologically relevant frequencyrange depending upon a selected neurological target. In someembodiments, a frequency range can be selected from about 100 Hz or lessto about 10 kHz. In other embodiments, different frequency ranges areused that may extend above, below, or above and below this range.Alternatively or in addition, a selected frequency range may be narrowerthan the exemplary range provided herein. The magnitude of the measuredimpedance |Z| is illustrated on a log-log scale, varying between about 6kΩ at 100 Hz and 800Ω at 1 MHz. The phase of the measured impedance ∠Zis illustrated across the same frequency span and ranges between about−80° and about −15°. The phase is negative, suggesting a capacitivereactance.

For the exemplary results measured, the minimum value of the magnitudeof the phase angle (i.e., the phase angle closest to 0°) occurs at about20 kHz. The absolute value of the phase angle increases at frequenciesabove and below 20 kHz. Thus, the impedance value at 20 kHz (i.e., |Z|=5kΩ, ∠Z=−15°) represents that impedance value of the measured valuesclosest to a pure resistance, as it has the smallest reactance. Thefrequency at which this measurement occurs, referred to herein as thepeak resistance frequency 149, is about 20 kHz. As each microelectrodesite generally displays different characteristics, a different peakresistance frequency may be obtained for one or more of themicroelectrodes.

Referring again to FIG. 3, the peak resistance frequency detector 137receives measured impedance values from the impedance analyzer 128(these values may be read from memory 134 when stored therein) andidentifies from these values a peak resistance frequency associated withthe measured impedance determined to be the closest to a pure resistor.The measured impedance value for each of the at least onemicroelectrodes 122 can be stored in memory 134 in a suitable datastructure, such as a table, including at least the measured compleximpedance phase angle and its associated frequency for each impedancespectroscopy sweep. A simple look up, or comparison operation can beperformed on the stored data to identify the phase angle having aminimum absolute value. The frequency associated with this value wouldbe the identified peak resistance frequency.

The executive process 131 initiates the stimulator 124 through theinstrument controller 138 to provide a stimulation signal at or aboutthe peak resistance frequency for the selected at least onemicroelectrode 122. By stimulating only at this frequency, orstimulating with a signal that has frequency components with bandwidthvery close to this frequency, the optimized stimulation of tissue isachievable for the selected at least one microelectrode 122. Theoptimized stimulation of tissue generally allows for optimal transfer ofelectrical charge to the tissue, with minimal signal distortion. Eachmicroelectrode site will generally display different characteristics,having a different peak resistance frequency.

Alternatively or in addition, the complex impedance can be used to setthe threshold or signal amplitude level for stimulation applied by thestimulator. Such a preferred threshold or signal amplitude level can beselected as being most adapted to stimulate the surrounding tissue atthat frequency. For example, if the tissue resistance at the PeakResistance Frequency is found to be 20 kΩ, then the stimulator mayadjust the stimulation signal amplitude in order to optimize the signalthat is being transmitted to the tissue. For example, if the tissueresistance is relatively low, the stimulator may lower the stimulationamplitude in order conserve battery life or limit damage. If the tissueresistance is high, the stimulator may increase the stimulationamplitude in order to reach an appropriate threshold potential requiredfor cellular stimulation. The relationship between the stimulationsignal amplitude level and measured tissue resistance can be determinedaccording to Ohm's Law. A greater applied current for the same tissueresistance will lead to an increased potential at themicroelectrode-tissue interface.

Alternatively, or in addition, the complex impedance can be used to setthe pulse shape applied by the stimulator. Such a preferred pulse shapecan be selected as being the most adapted to stimulate the surroundingtissue, at a physiologically relevant pulse frequency. For example, ifthe peak resistance frequency is found to be 20 kHz, then the stimulatormay adjust a predefined unipolar pulse shape, such as a square pulse, tohave a pulse width, equal to one half the inverse of the peak resistancefrequency. In this case, the pulse width would be adjusted to 25micro-seconds. A square pulse with this pulse width would have asubstantial spectral content at the Peak Resistance Frequency.

As another example, if the peak resistance frequency is found to be 20kHz, then the stimulator may adjust a predefined bipolar pulse shapesuch as a sine wave, or charge balanced pulses, with a substantialspectral content at or near the peak resistance frequency. The optimizedpulse shape generally allows for optimal transfer of electric charge tothe tissue, with minimal signal distortion. Each microelectrode sitewill generally display different characteristics, having a differentpeak resistance frequency, and may therefore require different preferredpulse shapes.

Alternatively or in addition, the complex impedance can be used tofilter the pulse shape applied by an existing stimulator. Such apreferred pulse shape can be selected as being the most adapted tostimulate the surrounding tissue, at a physiologically relevant pulsefrequency, or at a frequency that the stimulator can deliver. Forexample, if the peak resistance frequency is found to be 20 kHz, then afiltering mechanism can be used to reshape a predefined pulse shape(e.g., a 100 microsecond wide pulse), such as a unipolar square pulse,to have a major spectral content at the Peak Resistance Frequency.Optimized pulse re-shaping generally allows for optimal transfer ofelectric charge to the tissue, with minimal signal distortion. Eachmicroelectrode site will generally display different characteristics,having a different peak resistance frequency, and may therefore requiredifferent preferred pulse shapes. Although rectangular pulses arediscussed in the exemplary embodiments, it is envisioned that otherpulse shapes can be used, such as triangular, saw-tooth, trapezoidal,sinusoidal, raised cosine, and the like. In some embodiments, the shapeof the pulse itself can be filtered, for example changing a rectangularpulse to a trapezoidal pulse.

Referring to FIG. 6A, a cross-sectional view of an exemplarymicroelectrode-tissue interface is illustrated for a microelectrodeimplanted within brain tissue. Shown between the implanted device andthe bulk brain tissue is an encapsulation layer immediately surroundingthe implant. Generally, biological tissue reacts in response to animplanted device, such as the neurostimulation prosthesis. The tissuereaction initiates immediately following implantation of the prosthesisand continues for an initial reaction period after which the tissuereaction may slow or substantially cease altogether. For the exemplarybrain tissue-microelectrode interface, the tissue reaction has beenobserved to lead to an increase in astrocytes and microglia formingwithin the encapsulation layer over a period of about two weeksfollowing implantation. As the electrical impedance of themicroelectrode-tissue interface depends at least in part on the tissueimmediately surrounding the microelectrode, such variations due to thechanging encapsulation layer will result in corresponding variations tothe measured impedance. Experimental results have indicated a reductionin the peak resistance frequency during this initial reaction period.The peak resistance frequency essentially stabilizes at that time.Understanding this variation, the impedance measurements can be repeatedperiodically, especially during this initial reaction period to adjustthe stimulation frequency and thereby maintain efficient charge transferthroughout this period. After the initial reaction period, the impedancemeasurements can be performed periodically, but less frequently to tracklong term variations, and thereby maintain a proper peak resistancefrequency.

An equivalent circuit model can be used to closely simulate the behaviorof the electrode-tissue interface. FIG. 6B depicts an exemplary model ofthe interface. In an exemplary brain application, electrical impedanceof the brain tissue can be split into two different resistances: (i)R_(Bulk) representing a steady non-changing resistance, which describestissue not immediately affected by implantation damage and tissuereaction, and (ii) R_(Encapsulation) representing a resistance of thetissue immediately surrounding the implanted microelectrode, whichincreases as the tissue reaction due to implantation progresses. Theterm R_(Tissue) may be used for brevity, in whichR_(Tissue)=R_(Bulk)+R_(Encapsulation). The circuit element R_(ct)represents a charge transfer resistance, shown in parallel with constantphase element CPE_(DL) attributable to the double layer. The impedanceof a CPE can be approximated by

$Z_{CPE} = \frac{1}{{T\left( {j\;\omega} \right)}^{n}}$

A constant phase element acts like a capacitor when the value n=1, and aresistor when the value n=0. The circuit element C_(Parasitics) isformed between the metal traces and the electrolyte through theisolating material of the electrode. Other impedance components can beadded to the model, such as a Warburg Impedance or the trace resistance.However, the circuit elements illustrated in FIG. 6B contribute to mostof the impedance within the frequency range and voltage/currentamplitude applicable for such brain tissue applications.

Using this model, a simulation can be performed by choosing values forthe circuit model elements. A first exemplary model is simulated withparameters: R_(CT)=500 kΩ; R_(Bulk)=1 kΩ; R_(Encapsulation)=4 kΩ(therefore R_(Tissue)=5 kΩ); CPE_(DL)-T=100 nF; CPE_(DL)-n=0.8; andC_(Parasitics)=200 pF. The Peak Resistance Frequency is generallydetermined by finding the frequency at which the phase of theelectrode-tissue impedance is closest to CP. hi this first exemplarymodel, the Peak Resistance Frequency is found at about 20 kHz asdepicted in FIG. 5A and FIG. 5B.

The magnitude of the impedance is found to be about 5 kΩ at the PeakResistance Frequency, but this was pre-determined by choosingR_(Tissue)=5 kΩ. When performing a measurement the algorithm to findPeak Resistance Frequency would give the frequency at which to determinethe Impedance Magnitude of R_(Tissue). This magnitude can be used to setthe amplitude of the voltage or current used in stimulation. In thisway, the preferred amplitude for stimulation at or near the PeakResistance Frequency is determined.

There may be instances in which the algorithm to identify the PeakResistance Frequency is modified to avoid generating an incorrectresult. Such a case is appropriate for applications in which the phasecontribution of R_(CT) may be closer to zero than the phase contributionof R_(Tissue). Using the same equivalent circuit model as shown in FIG.6B, a second exemplary simulation can be performed, also using the sameparameters as the preceding exemplary model, but with CPE_(DL)-T=10 nF.This choice of parameter will make the impedance contribution fromR_(CT) more apparent over the frequency range being considered in theillustrative example, about 100 Hz to about 1 MHz. In this secondexemplary model, without modification, the Peak Resistance Frequencywould be found at 100 Hz as depicted in FIG. 5C and FIG. 5D. Althoughthe impedance value at 100 Hz has a phase closest to zero, it representsan erroneous result, because it is not related to the′ tissue (i.e.,R_(Tissue)). The signals delivered to the microelectrodes should be ator near the Peak Resistance Frequency due to R_(Tissue), and not R_(CT).In this instance the erroneous result can be avoided by noting that thephase at the correct Peak Resistance Frequency is the maximum of a peakin the phase.

Another method to avoid the erroneous result is to run the algorithmwithin a frequency range where it is known that the maximum would indeedonly be contributed by R_(Tissue). In this case, the frequency range forthe algorithm that would provide the correct result would be 1 kHz to 1MHz. Alternatively or in addition, relative peak resistive values of theimpedance can be identified along the sweep, and selecting the relativepeak having the highest frequency as the peak resistance frequency. Inthe illustrative example of FIG. 5A and FIG. 5B, two relative peakswould be identified: a first peak 151 at about 100 Hz and a secondrelative peak 148′ at about 60 kHz. Selection of the higher frequencypeak 148′ provides a Peak Resistance Frequency.

Referring to FIG. 7, a flow diagram of an exemplary process isillustrated for determining and stimulating a neurological target at apreferred stimulation frequency.

Operation.

As described in the flow diagram, the operation involves first measuringelectrical impedance of microelectrode-tissue interface at multipledifferent frequencies (150) for a respective microelectrode site. Animpedance analyzer circuit performs a frequency sweep and captures theimpedance spectrum of the microelectrode-tissue interface. Such ameasurement can be performed as a swept frequency measurement usingstandard impedance analyzer techniques. The most resistive impedancevalue is identified (160) from the impedance values measured at therespective microelectrode site. Measurement of the impedance anddetermination of the most resistive impedance can be repeated for othermicroelectrodes (170). Thus, such swept frequency measurements can beused to identify the optimum stimulation frequency, and/or optimum pulseshape, and/or optimum amplitude, for each microelectrode site.Thereafter, a stimulation signal is generated for at least one of theone or more microelectrode sites by tuning a stimulation source at,near, or about a peak resistance frequency or preferred pulse shapeassociated with the respective most resistive impedance (180).Alternatively, or in addition, the stimulation signal is generated witha preset, physiologically determined pulse frequency, e.g., a 100microsecond wide pulse at a pulse repetition rate of about 130 pulsesper second, having its pulse shape and/or amplitude tuned to anoptimized value based on the peak resistance frequency characteristics.The signal can be generated by a circuit attached to the microelectrodesite, or it can be filtered from an existing signal source, such as apulse generator. The tuned stimulation signal can then be applied to aneurological target through a respective microelectrode (190) foroptimal stimulation as described further herein.

Referring to FIG. 8, a functional block diagram of an exemplaryembodiment of a neurological target stimulator 200 configured in astimulation mode. The stimulator 200 includes an implantable portion 202including a microelectrode array 206 positionable at a neurologicaltarget. The implantable portion 202 also includes a signal generationdevice 208 for actively stimulating the neurological target. In someembodiments, each of the one or more microelectrodes of themicroelectrode array 206 is in communication with a dedicated signalgeneration device 208. In some embodiments, a signal filter 210 isprovided to modify one or more attributes of a signal generator output,such as a signal amplitude, pulse shape, and/or pulse width. Therespective stimulation signal is provided at an optimized frequency,pulse shape, or amplitude, for each individual microelectrode-tissueinterface, based on a peak resistance frequency. The implantable portion202 can include a power source 212, such as a battery. In someembodiments, the implantable portion 202 also includes a telemetry andcontrol module 214 configured for external communication with anextra-corporeal unit 204. Such a feature can be used to provideextra-corporeal control for operating the implantable portion 202.

Referring to FIG. 9, a functional block diagram of an exemplaryalternative embodiment of a neurological target stimulator 220 isillustrated configured in stimulation mode. The neurological targetstimulator 220 includes multiple microelectrodes 222 a, 222 b, . . . ,222 n (generally 222). The stimulator 220 also includes a controlcircuit 226 in communication with each of the microelectrodes 222through a respective signal generator 224 a, 224 b, . . . , 224 nconfigurable to provide a signal with characteristics based on the peakresistance frequency of the interconnected microelectrode site 222. Thesignal may be generated at or substantially near the peak resistancefrequency. Alternatively, the signal may be generated with apre-determined frequency, but its pulse shape is determined to have aspectral content equal to or near the peak resistance frequency.Alternatively, or in addition to, the amplitude of the signal can beadapted to the impedance magnitude at the peak resistance frequency.

Referring to FIG. 10, a functional block diagram of another exemplaryembodiment of a neurological target stimulator 230 is illustratedconfigured in so-called routing mode. The stimulator 230 includes animplantable portion 232 including a microelectrode array 236positionable at a neurological target. The implantable portion 232 alsoincludes a signal routing circuit 240 configured to direct a stimulationsignal to one or more of the microelectrodes 236 for activelystimulating the neurological target. In this embodiment, the stimulationsignal is obtained from a separate, implantable pulse generator 247. Thepulse generator 247 is in communication with the implantable portion 232through an interconnection cable 246 containing one or more signalleads. The implantable portion 232 also includes at least one signalconditioner 238 configured to condition an output signal from the pulsegenerator 247 suitable for stimulation of the neurological targetthrough one or more of the microelectrodes 236. The implantable portion232 generally includes a power source 242, such as a battery. In someembodiments, the implantable portion 232 also includes a telemetry andcontrol module 244 configured to communicate with an extra-corporealunit 234, to provide controls for operating the implantable portion 232.

Filtering of an Existing Signal.

In some embodiments, the signal conditioner 238 includes a filteringcircuit to pre-filter or gain adjust (e.g., pre-amplify and/orattenuate) or otherwise condition an existing signal before routing itto a microelectrode array. Several popular filter options includedigital filters, such as infinite impulse response (IIR) filters,electronic filters using one or more electrical components, such asinductors and capacitors, and surface acoustic wave (SAW) devices. Thefilters can be designed through well known filter synthesis techniquesto have a preferred performance features. Some of the controllablefeatures in filter synthesis include filtration bandwidth, cornerfrequency, pass-band ripple, and relative sideband level. Such filtersinclude categories referred to as Butterworth, Chebyshev 1 and 2, andElliptic filters. The particular implementation whether analog ordigital, passive or active, makes little difference as the output fromany implementation would still match the desired output. For anexemplary embodiment of a bandpass filter, the frequency response shownin FIG. 11A (magnitude) and FIG. 11B (phase) below, demonstrates afilter that would pre-filter a square wave signal in order to keep themost important elements of its frequency spectrum for a particularmicroelectrode site. The filter's center frequency (or pass band) Fc isselected at or near the peak resistance frequency of a respectivemicroelectrode.

Referring to FIG. 11 a schematic diagram of an exemplary embodiment ofan active bandpass filter is illustrated in electrical communicationbetween a stimulation source and at least one microelectrode. Theparticular resistor R1, R2 and capacitor C1, C2 values are selected tosynthesis performance of the active filter. Exemplary performance curvesfor the bandpass filter of FIG. 11 are illustrated in FIG. 12. Thefilter provides a pass band from about 600 kHz to about 1.8 MHz, with asubstantially linear phase response within this band.

An exemplary stimulation signal is illustrated in FIG. 13A, showing arepresentative square wave signal before and after filtering. The squarewave signal (dashed) has an amplitude varying between +2.5 and 0, with apulse width of about 100 μsecs. It is generally known that a square waveis a broadband signal. As described above, the square wave is filteredbefore being applied to a microelectrode site. The filtering processselects a portion of the frequency spectrum of the square wave, based ona desired output frequency. The solid signal 312 is a time-domainrepresentation of the resulting filtered signal. FIG. 13B demonstrateshow a pulse train of the exemplary filtered stimulation signals appears.The pulse frequency has been determined through physiologicalmechanisms. In this case the peak resistance frequency characteristicsof the microelectrode site is used to shape the pulse only, and not thepulse frequency, thereby optimizing charge transfer and minimizingsignal distortion. In some embodiments, the exemplary stimulation pulsemay be of negative amplitude, in which case the filter would function inthe equivalent manner and provide a negative output signal.

Referring to FIG. 14, a functional block diagram of an exemplaryalternative embodiment of a neurological target stimulator 250 isillustrated configured in stimulation mode. The neurological targetstimulator 250 includes multiple microelectrodes 252 a, 252 b, . . . 252n (generally 222). The stimulator 250 also includes a router circuit 256in communication with each of the microelectrodes 252 through a peakresistance frequency band filter circuit 254 a, 254 b, . . . 254 n(generally 254). An implantable pulse generator 258 provides a pulsesignal to the router circuit 256. The router circuit 256 directs theinput pulse signal to one or more of the selected microelectrodes 252through a respective peak resistance band filter circuit 254. Therespective peak resistance band filter circuit 254 is tunable to a peakresistance frequency of the associated microelectrode 252, which may bedetermined using techniques described herein. The filter circuit 254selects a sub-band of frequencies from the broadband input pulse signalthat include the respective peak resistance frequency. The filteredsignal is then applied to the neurological target through the respectivemicroelectrode 252. In the case of such filtered pulses, the pulserepetition frequency is not necessarily equivalent to, or near the peakresistance frequency. The pulse frequency will be predetermined. Thefilter circuit therefore only reshapes the pulse shape, to consist of amajor spectral content equal to or near the peak resistance frequency.Exemplary implantable pulse generators include the Medtronic SOLETRA™neurostimulator, commercially available from Medtronic Corp, MN.

A perspective view of a portion of a human anatomy is illustrated inFIG. 15, showing implantation of an exemplary neurological targetstimulator positioned for deep brain stimulation. A microelectrode probe264 is positioned at a neurological target 270 within a human brain 272.A portion of the electronics 268 may be implanted external to the brainto minimize invasion into the brain and/or to facilitate wireless accessthereto. Another portion of the electronics, such as a pulse generator262, is implanted at a remote portion of the subject's body, such aswithin the chest cavity as shown. A cable 266 is also implanted withinthe subject's body, and configured to interconnect the pulse generator262 to the electronics 268.

A top view of an exemplary embodiment of a microelectrode assembly 320is illustrated in FIG. 16. The assembly 320 includes an array ofmicroelectrodes 322 positioned along a distal end of an elongated probesubstrate 324. A first electronic assembly 328 is positioned at aproximal end of the elongated probe substrate 324. The first electronicassembly 328 can include one or more integrated circuit elements 321,such as a microprocessor, and one or more discrete electronic components332. The first electronic assembly 328 is interconnected to each of themicroelectrodes 322 through a respective trace 326 running along theelongated probe substrate 324. The electronic assembly 328 can beconfigured to implement one or more functions of the implantableneurological stimulator described herein. In some embodiments, theelongated probe substrate also includes at least a portion of theelectronic assembly 328.

In some embodiments, the first electronic circuitry 328 is connected toan implanted pulse generator (not shown) through a cable 334. In someembodiments, as shown, a second electronics assembly (or a portion ofthe first electronics assembly) includes telemetry circuitry 339, suchas a telemetry antenna. In the exemplary embodiment, at least a portionof electronic circuitry 328, 338 is positioned adjacent to themicroelectrodes 322, for example being joined by the elongated probesubstrate 324.

Mechanical Components.

The mechanical components and associated assembly processes serve tohouse the assembly 320 in a hermetic and biocompatible manner. They mayalso enable connection to an existing Implantable Pulse Generator or theextra-corporeal control unit. The extra-corporeal unit can providepower, programming ability, and retrieval of information. In someembodiments, the assembly 320 can be implanted much like currentlyavailable external cochlear stimulation systems. In an embodiment thatincludes an implantable pulse generator, it would serve to retrieveinformation and program the electrical unit to route the signals fromthe implantable pulse generator to the microelectrode array 322.

Microfabricated Components.

The device provides highly localized and efficient stimulation byincorporating microfabricated components, electronic components andmechanical components. The microfabricated component consists of amicroelectrode array. This array can be implemented in a polymericmaterial such as polyimide, polyurethane, parylene, or polysiloxane(silicone) and includes thin film or plated layers of a metal or metaloxide with high charge transfer capability such as platinum,platinum-iridium, iridium, iridium oxide or titanium. The polymeric andmetallic layers can be deposited sequentially and formed usingestablished principles of microfabrication such as spin coating, DC/RFsputtering, photolithography, plasma etching, and etching with a maskconsisting of a secondary or sacrificial material such as silicondioxide or photosensitive resist. The metallic layer can be formed tocreate the microelectrode arrays and traces which connect the array tothe electronics and housing. The polymeric layers serve to isolate thetraces from each other but also provide the structure of the implant'sstimulating/recording tip. There are several fabrication methods whichcan be described to build such a microfabricated component.

Electronic Components.

The electronic or microelectronic components of the device enable: (i)the ability to identify the peak resistance frequency for eachindividual microelectrode site using electrical impedance spectroscopy;(ii) stimulate at the characteristic peak resistance frequency of eachmicroelectrode (this guarantees minimized signal distortion and maximumcharge transfer to the tissue); or alternatively reshape the signal froman existing pulse generator to a preferred pulse shape; and (iii)stimulation and modulation of neuronal activity with the microelectrodearray and the ability to select which microelectrode sites arestimulating.

The electronics can be implemented using discrete components, integratedcircuit technology, digital signal processing (DSP), or a combination ofall three. The electronics can be incorporated in one unit, or can beused in conjunction with an existing implantable pulse generator (IPG).The electronics may include a telemetric programming interface toproperly condition or route the signal from the IPG to themicroelectrode array.

Referring to FIG. 17, a side view of an exemplary alternative embodimentof a microelectrode structure is illustrated. In this embodiment, anelectronics assembly 356 is positioned remote from the microelectrodearray 352. The microelectrode array 352 is joined to the electronicsassembly 356 through an arrangement of interconnecting electrical leads354. The electronics assembly 356 can be configured to implement one ormore functions of the implantable neurological stimulator describedherein. As illustrated, the electronics assembly 356 can also beconnected to an implanted pulse generator (not shown) through aninterconnecting cable 360. Alternatively or in addition, the electronicsassembly 356 can include telemetry circuitry for communicating with anexternal telemetry device 362.

The electronics assembly can include an electrical grounding lead forinterconnection to an electrical ground potential 358. In any of theembodiments described herein, impedance measurements and/or stimulationcan be implemented between two or more microelectrodes (e.g., adjacentmicroelectrodes). Alternatively or in addition, impedance measurementsand/or stimulation can be implemented between one or moremicroelectrodes and an electrical ground reference. Alternatively or inaddition, impedance measurements and/or stimulation can be implementedbetween one or more microelectrodes and the casing of the implantablepulse generator.

FIG. 18 is a flow diagram of an exemplary process for identifyingimplanted microelectrodes usable for stimulation of a neurologicaltarget. Neurological target sites can be chosen as those sitesdetermined to be actively stimulating. This can be accomplished bymonitoring neuronal activity at a variety of different target sites,identifying those target sites having neuronal activity, and simulatingthe identified sites.

In more detail, a microelectrode array can be implanted within an animalbody. The microelectrode array can be positioned at least partiallywithin a neurological target area, the extent of the array spanning aregion of the target. The array can take any of a number of variousforms, such as linear, curvilinear, planar, conformal, andthree-dimensional. Neuronal activity is measured at each microelectrodeof the microelectrode array (370). A neurological target is identifiedat those microelectrodes at which neuronal activity above some thresholdlevel (375). In some embodiments, the neuronal activity is recorded forsubsequent analysis. At least one of the microelectrodes at whichneuronal activity was observed are selected (380). The identifiedneurological target is subsequently stimulated using the at least oneselected microelectrodes (385).

In some embodiments, the microelectrode selection process is run oncesubsequent to implantation. In other embodiments, the microelectrodeselection process is repeated periodically to identify microelectrodespositioned at the target. As a neurological prosthesis may shift overtime, the microelectrode array is designed to be of sufficient expanseto accommodate for any anticipated repositioning of the implant. Thespacing between microelectrodes is selected to accommodate sufficientspatial resolution of the neurological target. In some embodiments, themicroelectrode selection process is repeated regularly, as part of acourse of treatment. That is to say, stimulation occurs responsive tomeasure neuronal activity.

Referring to FIG. 19, a functional block diagram of an exemplaryembodiment of a neurological target stimulator configured to observeneuronal activity and implement a microelectrode selection process, suchas the exemplary process described in relation to FIG. 18. The exemplaryneurological target stimulator 401 is essentially similar to theexemplary stimulator described in relation to FIG. 3, with the additionof a recorder 440. The sites that are actively stimulating are chosen asa result of the recording mode to simulate sites according to thepresence or lack of neuronal activity at the site. In the exemplaryembodiment, the recorder is coupled to one or more of themicroelectrodes 422 through the signal router 426. The recorder 440records neuronal activity at each of the interconnected microelectrodes.A microelectrode selection process 435 reviews the recorded neuronalactivity, identifying those microelectrodes at which activity above athreshold value is observed. Identified microelectrodes can be stored inmemory 434 and interconnected to other elements of the system, such asthe impedance analyzer 428 and stimulator 431 through the signal router426. Other functional elements, such as the peak resistance frequencydetector 437, instrument controller 438, executive process 441, andpower management 439 can operate as described herein.

In some embodiments, the processor 432 implements a state machine, suchas the exemplary state machine illustrated in FIG. 20. The state machinecan be used to select different operational modes of the stimulator 401as described in reference to FIG. 19. For example, in a first mode orstate, the stimulator 401 is configured to measure electricalneurological activity through the microelectrodes 422 of themicroelectrode array 420. In this mode, the processor 432 enables therecorder 440 and the signal router 426 to place the recorder 440 inelectrical communication with a selected one of the one or moremicroelectrodes 422. In a second mode or state, the stimulator 124 isconfigured to detect neurological activity indicative of theneurological target through one or more of the microelectrodes 422. Theneurological activity may be measured in terms of an electricalpotential, such as that produced by a synaptic potential of one or moreneurons in the vicinity of the target. Generally, a measured response ofthe individual microelectrodes 422 will differ dependent upon theirrelative position with respect to the target. In a third mode, the probeselector 435 identifies one or more of the microelectrodes 422positioned at or substantially near the intended target. The probeselector 435 in combination with the signal router 426 selects theidentified microelectrodes 422. In a fourth mode or state, thestimulator 431 is configured to stimulate the neurological target usingthe one or more selected microelectrodes 422. The stimulation can beprovided at a respective peak resistance frequency, or at an optimalpulse shape with respect to the peak resistance frequency, determined asdescribed herein. In the fourth mode of the exemplary state machine, theprocessor 432 disables the impedance analyzer 428 and enables thestimulator 431 prior to application of the stimulation signal.

In some embodiments, the same frequency sweep as performed for findingthe Peak Resistance Frequency can be used to identify anatomical targetsand determine which microelectrodes are placed in contact with thetarget, and which microelectrodes are not. Thereafter the stimulationsignals can be sent to the correct microelectrodes only. FIG. 21 is aflow diagram of an exemplary process for identifying implantedmicroelectrodes usable for stimulation of a neurological target usingsuch a process. Neurological target sites can be chosen as those sitesdetermined to be positioned at a neurological target by way of theirpeak resistance frequency. This can be accomplished by monitoring peakresistance frequency at a variety of different target sites, identifyingthose target sites having a relatively lower peak resistance frequency,and simulating the identified sites.

There are several differences between the anatomical areas of the brainthat can be identified using impedance spectroscopy. For exampledistinction between grey and white matter can be identified according toa measured difference between each material's respective electricalconductance. Also, certain areas of the brain may induce a moresubstantial tissue response to an implanted probe, such as from glialcells, therefore creating a denser cellular sheath around the implant.The microelectrodes implanted in such an area of greater tissue reactionwill register a lower Peak Resistance Frequency, a high impedancemagnitude at the frequency, or both. If the target area is known to havea greater tissue response, then the microelectrodes in the correct areacan be suitably identified and programmed to stimulate the targettissue. Likewise, if the targeted are is known to have a lesser tissuereaction than the surrounding region, then the microelectrodes in thisarea will have a higher Peak Resistance Frequency, a lower ImpedanceMagnitude at that frequency, or both. Therefore, the microelectrodes incontact with the targeted tissue can be similarly identified andprogrammed to stimulate the target tissue.

In more detail referring to FIG. 21, a microelectrode array can beimplanted within an animal body. The microelectrode array can bepositioned at least partially within a neurological target area, theextent of the array spanning a region of the target as described above(e.g., in relation to FIG. 18). Peak resistance frequency is measured ateach microelectrode of the microelectrode array (570). Such measurementscan be accomplished by any of the techniques described herein. Aneurological target is identified using impedance spectroscopy at thosemicroelectrodes for which a peak resistance frequency is measured belowsome threshold level (575). Microelectrodes lying outside of the targetwill not demonstrate a peak resistance frequency at this thresholdlevel. The difference in peak resistance frequency in differentneurological areas may be attributed to one or more of the difference inthe extent of the tissue reaction in the different neurological areas,or the difference in electrical tissue properties of the differentneurological areas. At least one of the microelectrodes, which isdetermined to be in the neurological target area is selected (580). Theidentified neurological target is subsequently stimulated using the atleast one selected microelectrodes (585).

Any of the devices and methods described herein can be used to treatsymptoms of movement disorders, such as Parkinson's disease, EssentialTremor or Dystonia. In the case of stimulating the hippocampus, suchtherapy can treat symptoms of Epilepsy. the devices and methodsdescribed herein can also be used as neurostimulation to treat otherparts of the body, such as the retina, the peripheral nervous system.

Various embodiments of neurological stimulation devices and techniqueshave been described herein. These embodiments are given by way ofexample and are not intended to limit the scope of the presentinvention. It should be appreciated, moreover, that the various featuresof the embodiments that have been described may be combined in variousways to produce numerous additional embodiments.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. An apparatus to stimulate a neurological target,comprising: a microelectrode; an impedance analyzer in electricalcommunication with the microelectrode, the impedance analyzer to measurea plurality of electrical impedance values at a microelectrode-tissueinterface across a plurality of frequencies; a preferred-frequencydetector in communication with the impedance analyzer, thepreferred-frequency detector to identify, based on the plurality ofelectrical impedance values measured at the microelectrode-tissueinterface across the plurality of frequencies, a peak-resistancefrequency; and a stimulation source in communication with at least oneof the microelectrode to generate a stimulation signal having a pulseshape based on the peak-resistance frequency, the pulse shape of thestimulation signal having at least one spectral component about thepeak-resistance frequency.
 2. The apparatus of claim 1, wherein themicroelectrode has dimensions approximating those of a cell, or a groupof cells, of the neurological target.
 3. The apparatus of claim 1,comprising: a plurality of electrical microelectrodes.
 4. The apparatusof claim 3, wherein the plurality of electrical microelectrodes isdisposed along an elongated support structure.
 5. The apparatus of claim1, comprising: at least one electrical filter in electricalcommunication between the stimulation source and the microelectrode. 6.The apparatus of claim 5, wherein the at least one electrical filter istunable to include a preferred frequency for the microelectrode.
 7. Theapparatus of claim 1, comprising: a respective electrical filter inelectrical communication between each of a plurality of microelectrodesand the stimulation source.
 8. The apparatus of claim 1, comprising: apulse generator; and an electrical filter in electrical communicationbetween the pulse generator and the microelectrode.
 9. The apparatus ofclaim 1, comprising: a signal router to establish a signal path betweeneach of a plurality of microelectrodes and the stimulation source. 10.The apparatus of claim 1, comprising: a sensor in communication witheach of a plurality of microelectrodes, the sensor to measure electricalsignals generated by neuronal activity.
 11. A method to stimulate aneurological target with at least one microelectrode, comprising:measuring, with an impedance analyzer in electrical communication with amicroelectrode, a plurality of electrical impedance values at amicroelectrode-tissue interface across a plurality of frequencies;identifying, by a preferred-frequency detector in communication with theimpedance analyzer, a peak-resistance frequency based on the pluralityof electrical impedance values measured at the microelectrode-tissueinterface; and generating, by a stimulation source in communication withthe microelectrode, a stimulation signal having a pulse shape based onthe peak-resistance frequency, the pulse shape of the stimulation signalhaving at least one spectral component about the peak-resistancefrequency.
 12. The method of claim 11, wherein the microelectrode hasdimensions approximating those of a cell, or a group of cells, of theneurological target.
 13. The method of claim 11, comprising: selecting apreferred stimulation frequency based on the plurality of electricalimpedance values measured at the microelectrode-tissue interface;receiving a broadband signal; selecting a spectral sub-portion of thebroadband signal, the spectral sub-portion including the preferredstimulation frequency; and stimulating the neurological target using thespectral sub-portion of the broadband signal.
 14. The method of claim13, wherein the broadband signal comprises a pulse generator signal. 15.The method of claim 11, comprising: measuring, with the impedanceanalyzer in electrical communication with a plurality ofmicroelectrodes, a corresponding plurality of electrical impedancevalues at a plurality of microelectrode-tissue interfaces.
 16. Themethod of claim 11, comprising: selecting at least one electrical filterin electrical communication between the stimulation source and themicroelectrode.
 17. The method of claim 11, comprising: tuning anelectrical filter based on the plurality of electrical impedance valuesmeasured at the microelectrode-tissue interface.
 18. The method of claim11, comprising: establishing a signal path between the microelectrodeand the stimulation source.
 19. The method of claim 11, comprising:selecting a preferred stimulation amplitude based on the electricalimpedance value measured at the microelectrode-tissue interface.
 20. Themethod of claim 11, comprising: selecting a preferred stimulationfrequency based on the plurality of electrical impedance values measuredat the microelectrode-tissue interface.